Bridge Funding - Genetic variant-based drug discovery targeting conserved pathways of aging

项目摘要/摘要(行政补编) 衰老是人类常见疾病最重要的危险因素，如糖尿病、心血管疾病 疾病和癌症。因此，针对衰老的基本机制而不是个别疾病是合理的 制定与年龄相关的多种疾病的治疗策略。为了测试这种方法的有效性 这个U19的研究人员利用阿尔伯特·爱因斯坦医学院的百岁老人资源 识别与人类极长寿相关的罕见基因变异，以确定潜在的药物靶点 促进健康老龄化。使用450名百岁老人和550名百岁老人的400个候选基因的重测序数据 我们在前一个资助期确定的控制措施，罕见的功能性遗传变异和相关 富含百岁老人的途径对健康长寿可能很重要，包括IGF-1，SIRT6， FOXO3a、NF-kB和SMAD3。重要的是，对555名百岁老人的新的、完整的外显子序列进行了分析 和508对照，提供了额外的候选变异体，例如BLM、USP35、UBE3C。一些稀有的 在人类ES细胞中进一步对变异候选进行了功能鉴定和评估，并进行了分化 血统。我们还生成了一些变体的小鼠模型，用于分析相关的表型 晚年人类健康，随后使用ES细胞和小鼠模型结果作为开发的先导 检测和测试针对受这些罕见变异影响的途径的小分子。有趣的是， 许多罕见的变异和/或受影响的通路可能与DNA损伤反应有关，包括 细胞衰老。基于我们方法证明的成功，我们现在已经扩展了我们的整个 外显子组测序的队列，以增加分析的稳健性，识别更多的变异和研究 通过RNA-seq的候选途径，使ESCs中的其他候选变体功能化，并生成 更多的老鼠模型。这将使我们能够极大地扩大有效治疗靶点的数量 药物开发。

PROJECT SUMMARY/ABSTRACT (ADMINISTRATIVE SUPPLEMENT) Aging is the most important risk factor for common human diseases, such as diabetes, cardiovascular disease, and cancer. Hence, targeting basic mechanisms of aging rather than individual diseases is a rational strategy to develop treatments of age-related multi-morbidity. To test the validity of this approach investigators in this U19 leverage the human centenarian resource at the Albert Einstein College of Medicine to identify rare genetic variants associated with extreme human longevity to identify potential drug targets for promoting healthy aging. Using resequencing data of 400 candidate genes in 450 centenarians and 550 controls we identified, in the previous funding period, rare, functional genetic variants and associated pathways enriched in centenarians and potentially important for healthy longevity, including IGF-1, SIRT6, FOXO3A, NF-kB and SMAD3. Importantly, analysis of new, whole exome sequences of 555 centenarians and 508 controls, provided additional candidate variants, e.g., BLM, USP35, UBE3C. A number of the rare variant candidates were further characterized and evaluated functionally in human ES cells and differentiated lineages. We also generated mouse models of some of the variants for analysis of phenotypes relevant for late-life human health and subsequently used the ES cell and mouse model results as leads for developing assays and testing small molecules targeting the pathways affected by these rare variants. Interestingly, many of the rare variants and/or affected pathways could be linked to the DNA damage response, including cellular senescence. Based on the demonstrated success of our approach we now have expanded our whole exome-sequenced cohort to increase robustness of the analysis, identify additional variants and study candidate pathways through RNA-seq, functionalize additional candidate variants in ESCs and generate more mouse models. This should allow us to greatly extend the number of validated therapeutic targets for drug development.